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CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

2022; American Association for the Advancement of Science; Volume: 8; Issue: 39 Linguagem: Inglês

10.1126/sciadv.abo0514

2375-2548

Paula Rodríguez-Márquez, María Eréndira Calleja-Cervantes, Guillermo Serrano, Aina Oliver‐Caldés, María Luisa Palacios-Berraquero, Ángel Martín-Mallo, Cristina Calviño, Marta Español‐Rego, Candela Ceballos, Teresa Lozano, Patxi San Martín‐Úriz, Amaia Vilas‐Zornoza, Saray Rodríguez-Diaz, Rebeca Martínez-Turrillas, Patricia Jáuregui, Diego Alignani, María C. Viguria, Margarita Redondo, Mariona Pascal, Beatriz Martín-Antonio, Manel Juan, Álvaro Urbano‐Ispizua, Paula Rodríguez‐Otero, Ana Alfonso Piérola, Bruno Paiva, Juan José Lasarte, Susana Inogès, Ascensión López-Dı́az de Cerio, Jesús F. San Miguel, Carlos Fernández de Larrea, Mikel Hernáez, Juan R. Rodríguez-Madoz, Felipe Prósper,

Viral Infectious Diseases and Gene Expression in Insects

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CAR High T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CAR High T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response.